Hepatitis C virus (HCV) is estimated to infect greater than 150 million people worldwide and is a major source of global morbidity and mortality. During the natural disease course of HCV infection, many individuals clear the virus after an acute viremia, while others develop chronic disease resulting in cirrhosis of the liver or hepatocellular carcinoma, but the factors that dictate these two disease phenotypes are poorly understood. Because abortive infections and/or clearance of acute infections occur within the first weeks after virus exposure, innate immunity, such as natural killer (NK) cell responses, are likely to play a significant role in dictating the disease course of viral hepatitis. Specific evidnce of a role for NK cells includes: (1) epidemiologic evidence demonstrating that individuals expressing alleles for the NK receptor KIR2DL3 and its ligand HLA-C have better clearance and control of HCV, (2) the most effective treatment for chronic HCV is therapeutic administration of interferon-, a cytokine known to activate and upregulate cytotoxic functions in NK cells, and (3) patients with more cytotoxic NK cell functions exhibit greater control of HCV replication. Unfortunately, experimental study of HCV in humans is significantly hindered by difficulty in accessing liver tissues and in identifying acutely infected individuals. Furthermore, the use of chimpanzees, the only other species in which HCV will replicate, is generally cost-prohibitive and the disease course is significantly attenuated. In this study we propose to investigate the role of NK cells in clearing Hepaciviruses using infection of common marmosets with a phylogenetically related virus, GBV-B, that induces a similar pathogenic disease course where many animals spontaneously clear the virus while others have persistent viral infection. This relatively inexpensive small primate model allows significant access to acute liver tissue samples and can be experimentally depleted of cytotoxic NK cells in vivo. With the ability to control for time of infection and superior access to acute samples and liver tissue we will test th central hypothesis that the quality and quantity of NK cell responses against Hepaciviruses play a major role in acute viral clearance versus chronic disease. Specifically we will investigate: (1) Are specific functional and phenotypic NK cell repertoires during acute and chronic GBV-B infection associated with viral clearance or progression to disease? and (2) Do cytotoxic NK cells inhibit GBV-B replication and contribute to control or resolution of GBV-B infection? A clearer understanding of these innate factors that lead to clearance of GBV-B and HCV infections could ultimately lead to development of new immunotherapeutics, drug regimens and vaccine modalities.